There is a definite and urgent need for improved imaging techniques for early detection and accurate staging of pancreatic cancer. Furthermore, targeted therapy, consisting of image guided chemotherapeutic drug release directed at the tumor site, will reduce harmful side effects on healthy cells, dramatically improving treatment efficacy while relieving patient suffering. Several imaging modalities are currently used to diagnose and stage pancreatic cancer. Primary methods include helical computed tomography (CT) and endoscopic ultrasound (EUS). Helical CT is generally used to initially detect the presence of a pancreatic mass and any distant metastasis, while EUS is used for tumor staging and predicting vascular invasion. EUS is a fine art and only highly experienced endosonographers who have performed at least 100 EUS examinations are generally trusted to evaluate and stage pancreatic cancer. Improving these EUS devices and ultimately the imaging of pancreatic tumors is critical for clinicians to properly assess patient treatment strategies. The overall goal of our research program is two-fold: 1) to develop molecular sensitive, targeted nanocage systems (NCSs) encompassing either imaging contrast agents, therapeutic agents, or both;and 2) to develop a sophisticated in-vivo imaging technology - endoscopic photoacoustic and ultrasound (EPAUS) imaging augmented with NCSs - that will allow for diagnosis, disease characterization and more precise staging of pancreatic cancer. The current project, however, is focused on development of both an intravenously injectable targeted NCS (with contrast agents only) and endoscopic photoacoustic and ultrasound imaging for early detection and reliable staging of pancreatic cancer. Therefore, the work proposed here aims to a) design and build the targeted, molecularly sensitive NCSs for EPAUS imaging of pancreatic cancer;b) design and build a laboratory prototype of the EPAUS imaging system;and c) initially demonstrate that the NCS-augmented EPAUS imaging can be used for early detection and accurate staging of pancreatic cancer. Elaborating on these three proposed aims, the core of NCS is a biodegradable polymer matrix of poly(lactic-co-glycolic) acid (PLGA). A silver nanocage will surround the polymer core and impart contrast agent properties for photoacoustic imaging. This nanocage will be shielded from the reticuloendothelial system by attachment of poly(ethylene glycol) (PEG) chains to the exterior. Finally, the entire system will be targeted by attaching antibodies, specific to pancreatic cancer antigens, also to the exterior. The final nanocage system will provide enhanced imaging of pancreatic cancer when used in conjunction with a custom designed EPAUS imaging device. The laboratory prototype of an EPAUS imaging device will be based on an endoscopic, linear array ultrasound probe interfaced with a multi-channel ultrasound imaging system and tunable pulsed laser source. Finally, the developed NCS-augmented EPAUS system will be tested using tissue-mimicking phantoms with cancer-simulating inclusions containing various concentrations of NCS, tissue culture cell phantoms, and xenographic mouse models of pancreatic cancer. The EPAUS images will be correlated with histological slides and compared with immunohistochemical analysis of tissue samples. PUBLIC HEALTH RELEVANCE: There is a definite and urgent need for improved imaging techniques for early detection and accurate staging of pancreatic cancer. Furthermore, targeted therapy, consisting of image guided chemotherapeutic drug release directed at the tumor site, will reduce harmful side effects on healthy cells, dramatically improving treatment efficacy while relieving patient suffering. Several imaging modalities are currently used to diagnose and stage pancreatic cancer. Primary methods include helical computed tomography (CT) and endoscopic ultrasound (EUS). Helical CT is generally used to initially detect the presence of a pancreatic mass and any distant metastasis, while EUS is used for tumor staging and predicting vascular invasion.